Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A flip of the mitotic spindle has disastrous consequences for epithelial cells

22.07.2013
Stowers investigators use genetics and live cell imaging to illuminate molecular mechanisms that position the cell division machinery in growing tissues

Constructing a body is like building a house—if you compromise structural integrity, the edifice can collapse. Nowhere is that clearer on a cellular level than in the case of epithelial sheets, single layers of cells that line every body cavity from the gut to mammary glands. As long as epithelial cells pack tightly and adhere to their neighbors, the cellular business of building tissue barriers and constructing ducts goes smoothly. But if epithelial cells fail to hold together, they die, or worse, produce jumbled masses resembling tumors known collectively as carcinomas.

Stowers Institute for Medical Research Associate Investigator Matt Gibson, Ph.D., and his team use simple animal systems like fruit flies and sea anemones to investigate how epithelial cells maintain order while getting jostled by cell division.

New findings from his lab published in the July 21 advance online issue of Nature demonstrate that the way the mitotic spindle—the machinery that separates chromosomes into daughter cells during cell division—aligns relative to the surface of the cell layer is essential for the maintenance of epithelial integrity. It also hints at a surprising way that cells initiate a gene expression program seen in invasive cancers when that process goes awry.

The study employs live imaging of fruit fly imaginal discs, simple larval tissues that ultimately give rise to the adult wing. "In a culture dish, cells can divide willy nilly," says Gibson. "But in an organism cell division must be reconciled with the broader structural context. Our work is addressing how epithelial tissues maintain structural integrity, even during the extreme events of cell division."

The starting point for this work was the lab's 2011 Current Biology paper showing that when columnar cells packed in an epithelium divided, their upper (apical) end briefly ballooned out to allow the cell's nucleus to move into that region. As division began, the mitotic spindle (which faithfully distributes chromosomes into each daughter cell) invariably oriented itself parallel to the apical surface of the epithelium.

In other words, if you pointed a tiny camera in your gut toward dividing epithelial cells of its lining, you would "see" the mitotic spindle looking like a symmetrical web, exactly like it did in your high school biology textbook.

To determine why its orientation was non-random, the group did an equivalent experiment. Using high resolution fluorescence imaging to look inside dividing cells in developing wing discs, they observed that the two poles of the spindle were always near the septate junctions, specific regions of close molecular contact between neighboring cells. Two junction components, proteins called Discs Large and Scribble, were juxtaposed to the spindle, suggesting they might act as cues to orient it.

The seemingly odd names given to these factors decades ago reflect what biologists saw in fly mutants lacking each protein. In flies without Discs Large, the imaginal discs are massively overgrown, while fly embryos lacking Scribble resemble a chaotic scribble reminiscent of a tumor. Gibson reasoned that the reported tumor-suppressive activity of these proteins might be linked to a role in keeping the mitotic spindle in line.

So his group genetically deleted Scribble, Discs Large and a host of other factors in wing disc cells and watched what happened when cells divided, an effort aided by a customized microscope built by the Stowers Microscopy Center. What they saw was dramatic: Scribble deletion caused the mitotic spindle to flip over at a random angle, as did deletion of Discs Large. Next, by directly perturbing the spindle, the researchers video-captured the process by which cells with misoriented spindles began to peel away, or delaminate, from the epithelium.

"I did not expect that spindle orientation defects could be sufficient to cause loss of epithelial identity," explains Yu-ichiro Nakajima, Ph.D., a postdoctoral fellow in the Gibson lab and the study's first author. "But people in the field have hypothesized that spindle misorientation might cause tumorigenesis or even contribute to cancer development."

Initially, the group did not observe such dire consequences: Gibson says that delaminating cells generally "fall out of the epithelium" and are killed off by apoptosis, a mechanism healthy tissues use to eradicate damaged cells. But when the team experimentally inhibited apoptosis, tumor-like growths emerged at the base of the cell layer. Cells in those growths expressed genes switched on in invasive human tumors, among them the fruit fly version of human Matrix metalloproteinase-1, an epithelial cancer biomarker.

"The findings derived from epithelial biology often lead to a better understanding of cancer development," says Nakajima. "We have found that spindle orientation has a tumor-suppressive role in proliferating epithelia. So we are looking for other spindle regulators that may represent novel tumor suppressors."

Human epithelial cells do express mammalian Scribble and Discs Large proteins, and both play key roles in maintaining epithelial cell polarity, or shap—a property lost in metastatic cancer cells. Whether Scribble or Discs Large act as tumor suppressors in human cancers is under investigation.

Gibson urges caution in comparing regulation of Drosophila and human epithelia. Nonetheless he notes that normal tissues in both flies and humans protect themselves by killing off misbehaving cells via apoptosis. If that mechanism failed, as is frequently observed in human cancers, disordered cells within an epithelium could escape.

"When cells are basically imprisoned in an epithelial layer, things stay nicely organized," says Gibson. "But in this study we found that simply forcing a cell to delaminate from an epithelium is enough to initiate an abnormal gene expression program. That means that maintaining an ordered structure is not just a physical requirement but could also protects cells from switching on potentially aberrant genes."

Other contributors were Emily Meyer from the Gibson lab, and Amanda Kroesen and Sean McKinney, Ph.D., from the Stowers Microscopy Center.

The study was funded by the Stowers Institute for Medical Research and the Burroughs Wellcome Fund.

About the Stowers Institute for Medical Research

The Stowers Institute for Medical Research is a non-profit, basic biomedical research organization dedicated to improving human health by studying the fundamental processes of life. Jim Stowers, founder of American Century Investments, and his wife, Virginia, opened the Institute in 2000. Since then, the Institute has spent over 900 million dollars in pursuit of its mission.

Currently, the Institute is home to nearly 550 researchers and support personnel; over 20 independent research programs; and more than a dozen technology-development and core facilities.

Gina Kirchweger | EurekAlert!
Further information:
http://www.stowers.org

More articles from Life Sciences:

nachricht Two Group A Streptococcus genes linked to 'flesh-eating' bacterial infections
25.09.2017 | University of Maryland

nachricht Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: LaserTAB: More efficient and precise contacts thanks to human-robot collaboration

At the productronica trade fair in Munich this November, the Fraunhofer Institute for Laser Technology ILT will be presenting Laser-Based Tape-Automated Bonding, LaserTAB for short. The experts from Aachen will be demonstrating how new battery cells and power electronics can be micro-welded more efficiently and precisely than ever before thanks to new optics and robot support.

Fraunhofer ILT from Aachen relies on a clever combination of robotics and a laser scanner with new optics as well as process monitoring, which it has developed...

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Fraunhofer ISE Pushes World Record for Multicrystalline Silicon Solar Cells to 22.3 Percent

25.09.2017 | Power and Electrical Engineering

Usher syndrome: Gene therapy restores hearing and balance

25.09.2017 | Health and Medicine

An international team of physicists a coherent amplification effect in laser excited dielectrics

25.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>